Writing in the April 9, 2008 issue of the Journal of the American Medical Association, Dr Barbara V Howard (Medstar Research Institute, Hyattsville, MD) and colleagues note that while the use of a surrogate end point—in this case, change in carotid intima media thickness (IMT)—is not a substitute for hard clinical events, the findings support the idea that an aggressive two-pronged approach may be particularly beneficial in diabetics. Importantly, the changes were seen in patients who had had no previous cardiovascular events.

The study looked exclusively at American Indian men and women with type 2 diabetes, hypertension, and dyslipidemia.

According to Howard, this group was chosen because the LDL and blood-pressure targets have been previously validated in this population, while the carotid IMT and echocardiography measures have been shown to predict future events in this group.

"We have also found over the years that studying American Indians with diabetes has been extremely relevant because this is a population that has classic type 2 diabetes; they've just had it longer, and so we know more about them," she said.

"And now that there's an epidemic all through the US, what we've learned has been very valuable."

Patients were randomized to drug treatment to reach the standard targets of 100 mg/dL or lower for LDL and 130 mm Hg or lower for systolic blood pressure (SBP) or to a more aggressive target of 70 mg/dL or lower for LDL and 115 mm Hg or lower for SBP.

Howard et al report that, while both groups were successfully treated to their respective LDL and SBP targets over 12 months and both experienced similarly low rates of cardiovascular events, only patients in the aggressive target group experienced regression of atherosclerosis by IMT.

Likewise, patients in the aggressive target group also experienced greater decreases in left ventricular mass, as measured by echocardiography.

According to Howard, the atherosclerosis changes appeared to be linked to the LDL lowering, as other studies have shown, while the LV changes likely occurred in response to lower SBP.

"In our secondary analyses, we showed that the reduction in IMT was largely due to the LDL reduction.

It's hard to tease that out, but from the models we've set up it looks to us that the LDL drop is driving the reduction in atherosclerosis, and the blood-pressure change was largely responsible for the improvement in the size of the heart."

While the study implies that there are greater gains to be had by treating diabetics to even lower LDL and SBP goals, Howard emphasizes that only a small number of clinical events occurred even in patients treated to standard targets.

"Our study suggests that treating even to the standard targets, which most diabetics don't reach, is going to be very effective, although we need to look for longer, in more people, to be sure that the improvements that we saw in the neck vessels and in heart function will translate into lower events," she said.

"The key is going to be cost/benefit. If, in fact, you could maintain that low rate of events in the standard group, that might be enough. In other words, if you control both their major risk factors, is it really worth the effort and money to go much lower? And is it worth the risks?"

In SANDS, rates of adverse events associated with drug therapy were higher in the more aggressively treated group, although rates of serious adverse events were no different.

"There are some side effects, and you can't know in advance if these would become more of a problem over time," she told 

1. Howard BV, Roman MJ, Devereux RB, et al. Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: The SANDS randomized trial. JAMA 2008; 299:1678-1689.